Sandramycin (1) is a natural product having potent antitumor antibiotic activity. Sandramycin has been structurally characterized through spectroscopic and chemical degradation studies. Sandramycin constitutes one of the newest members of a growing class of cyclic decadepsipeptides including luzopeptins A-C and E.sub.2, quinaldopeptin and guinoxapeptins A and B which possess potent antitumor, antiviral, and antimicrobial activity (FIG. 1; Matson, et al. J. Antibiot. 1989, 42, 1763; Matson et al. J. Antibiot. 1993, 46, 162; Ohkuma et al. J. Antibiot. 1980, 33, 1087; Tomita et al. J. Antibiot. 1980, 33, 1098; J. Antibiot. 1981, 34, 148; Konishi et al. J. Am. Chem. Soc. 1981, 103, 1241; Arnold et al. J. Am. Chem. Soc. 1981, 103, 1243; Toda et al. J. Antibiot. 1990, 43, 796). Characteristic of this class of agents, sandramycin possesses a two-fold axis of symmetry and two heteroaromatic chromophores that results in sequence-selective DNA bis-intercalation spanning two base-pairs preferentially at 5'-AT sites. In this respect, the agents are functionally related to the quinoxaline antitumor antibiotics including echinomycin and triostin A which also bind to DNA by bis-intercalation but with a substantially different sequence selectivity (5'-CG versus 5'-AT).
The cytotoxic activity of luzopeptin A and sandramycin has been shown to be 100-300 times greater than echinomycin and smoothly declines in the series with luzopeptin A&gt;B&gt;C. A reverse order of antiviral activity was observed with luzopeptin C&gt;B&gt;A in inhibiting human immunodeficiency virus (HIV) replication in vitro. Notably, this is observed at noncytotoxic concentration for luzopeptin C through inhibition of HIV reverse transcriptase (Take et al. J. Antibiot. 1989, 42, 107; Inouye et al. J. Antibiot. 1987, 40, 100). The recent disclosure of the quinoxapeptins as potent inhibitors of HIV-1 and HIV-2 reverse transcriptase that are equally active against two resistant single mutants and a double mutant of HIV-1 reverse transcriptase has increased the interest in this class of agents especially since they were found not to inhibit human DNA polymerase .alpha., .beta., .gamma., and .delta. at comparable concentrations (Lingham et al. J. Antibiot. 1996, 49, 253).
What is needed are analogs of sandramycin having enhanced cytotoxic activities against various tumor cell lines and sandramycin analogs having inhibitatory activity against reverse transcriptase. Furthermore, what is needed are active analogs of sandramycin which can be synthesized from economically accessable sources.